A major challenge in vaccinology is that the efficacy of a vaccine can only be ascertained retrospectively, upon infection. The identification of molecular signatures induced rapidly after vaccination which correlate with and predict, the later development of protective immunity, would represent a strategy to prospectively determine vaccine efficacy. Such a strategy would be particularly useful when evaluating the efficacy or immunogenicity of untested vaccines, or in identifying individuals with sub-optimal responses amongst high risk populations such as the elderly. We have recently used a systems biology approach to identify early gene signatures that predict later immune responses in humans vaccinated with the yellow fever vaccine YF- 17D. The goal of the present application is to determine extent to which such an approach will have broad utility in predicting the immunogenicity of other vaccines, and in identifying new correlates of protective immunity. To achieve this goal we have initiated a highly collaborative effort to perform a comprehensive analysis of immune responses induced by three distinct vaccines: (i) the inactivated trivalent influenza vaccine, (ii) the pneumococcal polysaccharide vaccine and (iii) the live attenuated varicella-zoster vaccine. These three vaccines were selected for this study because influenza virus, pneumococcus and zoster, are of global public health importance and the cause of severe morbidity and mortality, especially in the elderly and other high-risk groups. In addition, all three of these vaccines are known to generate sub-optimal immunity in a substantial proportion of elderly vaccinees. Defining the innate signatures in these sub-optimal responders may provide insight into the defects that underlie poor vaccine efficacy and immunogenicity in the elderly. The program is organized into two Research Projects: 1. Innate signatures (Pulendran), and 2. Adaptive Immunity (Ahmed). These will be supported by an Adminstrative Core (Pulendran), a Clinical Core (Mulligan), an Epitope Mapping Core (Sette), and a Computational Core (Haining). The successful completion of this program may provide insights into the defects that underlie poor vaccine efficacy in the elderly, and establish the broad utility of systems biology in predicting vaccine immunogenicity.